Pustular psoriasis: Management

INTRODUCTION — 

Pustular psoriasis is an uncommon subtype of psoriasis that may present as a generalized pustular skin eruption (generalized pustular psoriasis [GPP]) or a localized pustular skin eruption (acrodermatitis continua of Hallopeau and palmoplantar pustulosis) (picture 1A-C). The goals of treatment of GPP are to improve skin manifestations, to alleviate associated systemic symptoms, and to minimize risk for life-threatening systemic complications. Treatment of localized pustular psoriasis is indicated to minimize the development of bothersome or disabling symptoms.

The treatment of GPP and localized pustular psoriasis will be reviewed here. The clinical features of pustular psoriasis, the management of pustular psoriasis in pregnant women (impetigo herpetiformis), and the management of other forms of psoriasis are reviewed separately. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis" and "Dermatoses of pregnancy" and "Chronic plaque psoriasis in adults: Overview of management" and "Psoriasis in children: Management of chronic plaque psoriasis" and "Guttate psoriasis".)

GENERALIZED PUSTULAR PSORIASIS

Disease overview — Generalized pustular psoriasis (GPP) is characterized by the development of a widespread eruption of pustules and erythematous plaques (picture 1A-C). A preceding history of psoriasis may or may not be present. The acute variant (also known as generalized pustular psoriasis of von Zumbusch) is characterized by the sudden onset of a pustular eruption accompanied by fever and malaise. Laboratory abnormalities, such as leukocytosis, an elevated erythrocyte sedimentation rate, hypocalcemia and other electrolyte abnormalities, hypoalbuminemia, and elevated liver enzymes, are common. In addition, serious complications, including sepsis and hepatic, respiratory, or renal dysfunction, can occur [1-4]. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Generalized pustular psoriasis'.)

GPP may also present as a less acute disorder in which patients develop widespread, annular or figurate, erythematous plaques with peripheral pustules and scale (generalized annular pustular psoriasis) [4,5]. Pain and fever may accompany these cutaneous manifestations. Generalized annular pustular psoriasis is a common presentation of pustular psoriasis in children. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Epidemiology'.)

There is no cure for GPP, and recurrences are common [4]. Thus, long-term treatment is often required to minimize recurrences of disease.

Approach to therapy — Determining the optimal approach to treatment is complicated by the lack of high-quality data on the efficacy of treatments for GPP. Data on treatment primarily consist of retrospective studies, case reports, and expert opinion, with most studies originating from a single country (Japan). Interpretation of the available data is further compromised by the lack of a validated grading system for the severity of GPP, and the absence of a standardized method of assessing the response to treatment [6].

The approach described in this topic reflects our preferred approach based upon review of the literature and clinical experience; other approaches may also be reasonable. In Japan, multiple therapies are approved for the treatment of GPP. Regulatory bodies in the United States and European Union have not approved any therapies for GPP.

The treatment approach reviewed below focuses on nonpregnant adults with GPP. The treatment of GPP in pregnant women and children is reviewed separately. (See "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy' and 'Children' below.)

Increasing knowledge about the pathogenesis of GPP associated with IL36RN mutations may lead to new therapeutic options for this form of GPP. (See 'IL36RN mutations' below and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Genetics'.)

Important interventions — Our approach to treatment consists of the following key steps:

●Determine need for hospitalization and supportive care – Patients with acute GPP usually appear systemically ill, and admission to the hospital often is necessary to ensure adequate supportive care. The decision to hospitalize a patient is made based upon global consideration of the severity of illness, vital sign stability, fluid and electrolyte status, and concern for systemic infection.

Supportive skin care measures may help to soothe skin symptoms in patients with GPP. Use of moisturizers, wet wraps, and/or oatmeal baths can be beneficial in patients with this disease [1].

●Identify and discontinue the causative drug (in drug-induced cases) – The withdrawal or administration of a variety of drugs has been linked to the development of GPP. In general, the causative agent should be discontinued, provided this can be done safely. There is at least one report of successful management of GPP without discontinuation of the inciting medication [7].

Systemic glucocorticoids are commonly cited contributors [4]. However, there is insufficient evidence to confirm the best way to discontinue systemic glucocorticoids in patients with glucocorticoid-induced GPP. Options include maintaining the glucocorticoid dose until disease control is achieved with other therapies and continuing to taper the systemic glucocorticoid during the initiation of GPP therapy. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Precipitating factors'.)

Patients in whom GPP was precipitated by an antipsoriatic drug may be best managed with an agent with a different mechanism of action. For example, the tumor necrosis factor (TNF)-alpha inhibitor infliximab would be a less favorable choice for a patient with adalimumab-induced GPP.

●Initiate treatment to control skin disease – Medical treatment options for GPP consist of systemic therapies, topical therapies, and phototherapy. We typically use systemic treatment for the initial management of adults because phototherapy tends to have a delayed onset of action and topical therapies are impractical for widespread disease. In addition to limiting factors, such as drug availability and patient-specific contraindications, the selection of an initial systemic therapy is based upon the acuity and severity of disease. Topical therapies primarily serve as adjuncts to systemic therapy in adults with GPP. (See 'First-line pharmacologic therapy for adults' below and 'Adjunctive topical therapy' below.)

●Manage extracutaneous complications – Extracutaneous complications, such as sepsis or internal organ dysfunction, should be managed appropriately. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical course'.)

First-line pharmacologic therapy for adults — Our preferred first-line treatments for nonpregnant adults include acitretin, methotrexate, cyclosporine, and various biologic therapies [8-11]. The approach to treatment selection differs for patients with tolerable, nondisabling disease and patients with severe, acute disease. (See 'Tolerable, nondisabling disease' below and 'Severe, acute disease' below.)

Tolerable, nondisabling disease — Acitretin and methotrexate are the preferred initial treatments for adults with relatively stable GPP. Advantages of these drugs include that they are relatively well tolerated, available in oral form, and can be used for long-term maintenance treatment. A disadvantage is their relatively slow onset of action; thus, an alternative approach is indicated for patients with more severe disease. (See 'Severe, acute disease' below.)

Data are insufficient to compare the efficacy of acitretin and methotrexate. Selection between these drugs is based upon patient-specific factors, such as ability to tolerate side effects and contraindications. As an example, the requirement that women abstain from pregnancy for three years after acitretin treatment gives acitretin a relative contraindication for use in women of childbearing age.

Oral retinoids — Oral retinoids that have been used for GPP include etretinate, acitretin (a metabolite of etretinate), and isotretinoin. Acitretin is our preferred oral retinoid because clinical experience with isotretinoin for this indication is more limited, and etretinate was withdrawn from United States market in 1998:

●Administration and precautions – Our usual starting dose for acitretin is 0.75 to 1 mg/kg per day. Japanese guidelines have suggested an initial dose of etretinate of 0.5 to 1 mg/kg per day [12]. Improvement (ie, cessation of new pustule formation and initial improvement in other clinical signs) is usually noted within 7 to 10 days of oral retinoid therapy, and a complete response often requires two to three months of treatment. After disease control is achieved, the dose of acitretin can be tapered slowly to the lowest dose necessary to maintain improvement.

Examples of adverse effects of oral retinoids include xerosis, cheilitis, dry mucous membranes, hypertriglyceridemia, hair loss, liver function test abnormalities, bone changes, and visual changes. Oral retinoids are teratogenic and pregnancy should be avoided for three years following acitretin therapy. Therefore, the drug has a relative contraindication for women of childbearing age.

●Efficacy – Evidence to support retinoid use is limited. Some support comes from a Japanese study that analyzed treatment data from 385 patients with acute GPP obtained through questionnaire responses from multiple community center hospitals [13]. The study found that among 188 patients treated with retinoids, treatment was reported as effective in 84 percent. Retinoid treatment regimens were not standardized; typically, treatment was with etretinate (1 mg/kg per day and tapered as tolerated). Many patients received retinoids in combination with other therapies. Data from a retrospective study also suggests benefit of etretinate [14].

In a series of 11 adults with GPP, isotretinoin therapy seemed beneficial for improving pustule formation in 10 patients, although monotherapy with the drug did not seem to be effective for clearing all lesions [15]. Isotretinoin also appeared useful in an adolescent female who failed to respond adequately to topical corticosteroids and methotrexate [16] and in two patients who did not tolerate acitretin [17].

Methotrexate — Methotrexate may be given subcutaneously or orally and appears to be effective for GPP:

●Administration and precautions – A typical dose of methotrexate for adults with GPP is 15 mg per week, with a maximum dose of 25 mg per week. Methotrexate is not given daily. We often use subcutaneous, rather than oral, methotrexate given that absorption of oral methotrexate may be reduced at higher doses and bioavailability may be superior with subcutaneous dosing [18-20]. Significant clinical improvement is expected within 8 to 12 weeks.

Myelosuppression is a potential serious adverse effect of methotrexate that warrants careful administration of treatment and laboratory follow-up. The amount of methotrexate used for the initial dose varies among experts, with some experts initiating with a small test dose (eg, 5 mg per week) followed by upward titration of the dose and others initiating at higher doses (eg, 15 mg per week) [21]. When treating older adult patients or patients with renal insufficiency, the initial dose should not exceed 10 mg per week.

Additional adverse effects of methotrexate include gastrointestinal distress, hepatotoxicity, pulmonary toxicity, and teratogenicity. Methotrexate should be combined with folic acid supplementation (eg, 1 mg of folic acid per day) to decrease hematologic and gastrointestinal toxicity [22]. (See "Major adverse effects of low-dose methotrexate".)

Monitoring protocols for methotrexate treatment vary; in general, a complete blood count with differential and platelets should be performed at baseline and soon after the initiation of methotrexate and following dose increases. While some clinicians perform hematologic testing approximately one week after dose initiation or changes, others (including the author) perform tests after two to four weeks provided the patient is not an older adult individual and does not have renal insufficiency. Hematologic testing is repeated every two to four weeks during the first few months of treatment and is subsequently tapered to every one to three months. Periodic laboratory monitoring of kidney and liver function is also indicated during methotrexate therapy.

●Efficacy – Data on the efficacy of methotrexate are limited. In a multicenter study in Japan in which community hospitals were sent questionnaires about patients with GPP, efficacy of methotrexate was documented for 76 percent of 41 patients given this therapy alone or in conjunction with other therapies [13]. In addition, in a retrospective study of 63 patients hospitalized for GPP at Mayo Clinic affiliated-hospitals between 1961 and 1989, good responses to methotrexate were reported for three of eight patients with acute GPP and both of two patients with annular pustular psoriasis [14].

Severe, acute disease — For patients with severe, acute disease that warrants rapid stabilization and improvement, we select faster-acting drugs, such as cyclosporine, infliximab, and anti-interleukin (IL) 17 or anti-IL-23 biologic agents.

Treatment selection — Cyclosporine and infliximab have a longer history of use for GPP compared with anti-IL-17 and anti-IL-23 biologic agents and, historically, were considered the treatments of choice for severe, acute GPP. The emergence of reports suggesting benefit of anti-IL-17 and anti-IL-23 biologic agents has led to the inclusion of these drugs as first-line therapies for GPP [8,23].

Data comparing therapies for GPP are limited and insufficient for determining relative efficacy. Practical advantages of biologic IL-17 and IL-23 inhibitors include a more favorable side effect profile than cyclosporine and subcutaneous route of administration (in contrast to the intravenous administration of infliximab).

Because rapid initiation of therapy is necessary for patients with severe, acute GPP, treatment availability often influences the selection of an initial treatment. Although we generally prefer to use a biologic anti-IL-17 or anti-IL-23 drug for initial therapy, we often find it necessary to use cyclosporine or infliximab for hospitalized patients because of greater availability of these drugs in the inpatient setting.

Once control of acute disease is achieved, patients may be maintained on fast-acting therapies or transitioned to acitretin or methotrexate for long-term treatment. Cyclosporine is the exception; risk for serious side effects with prolonged cyclosporine therapy supports transitioning to other treatments.

Cyclosporine — Oral cyclosporine has a long history of use for psoriasis and can induce rapid improvement of GPP:

●Administration and precautions – Effective doses of cyclosporine for adults with GPP have ranged from 2.5 to 5 mg/kg per day [24]. We typically treat severe, acute GPP with 4 to 5 mg/kg (ideal body weight) per day. Marked improvement often occurs within the first few days of treatment [1,25-27]. Because side effects of cyclosporine are a concern, once disease control is achieved, we attempt to taper the dose over the course of two to three months and transition to other treatments.

Potential adverse effects of cyclosporine include hypertension, renal toxicity, and increased risk for infections and malignancy. Laboratory tests as well as blood pressure should be monitored closely during therapy. Adverse effects of cyclosporine are discussed in greater detail separately. (See "Pharmacology of calcineurin inhibitors", section on 'Side effects'.)

●Efficacy – Despite the common use of cyclosporine for severe, acute GPP, data on the efficacy of the drug are limited. A beneficial effect of cyclosporine is supported by retrospective data obtained from hospitals in Japan that suggested treatment efficacy in 60 to 70 percent of patients treated with cyclosporine alone or in conjunction with other therapies [13,28].

Infliximab — Infliximab is a TNF-alpha inhibitor given through intravenous infusion that may lead to rapid improvement in GPP:

●Administration and precautions – Standard dosing of infliximab for psoriasis in adults is intravenous infusion of 5 mg/kg at weeks 0, 2, and 6, and every six to eight weeks thereafter. Marked improvement is usually evident within several days.

Infliximab may be continued for long-term management of GPP after control of acute disease is achieved. Alternatively, patients can be transitioned to other therapies.

Potential adverse effects of infliximab include infusion reactions and increased risk for infection (including herpes zoster), malignancy, heart failure, and demyelinating disease [29,30]. Patients should be evaluated for latent tuberculosis and hepatitis B prior to initiating therapy.

There are also reports of infliximab inducing psoriatic eruptions, including GPP [7,31,32]. The adverse effects of infliximab are reviewed separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

●Efficacy – The use of infliximab for GPP is based upon case reports and observational studies that suggest efficacy of this treatment [8,30,33-43].

Among 10 patients in whom flares of acute GPP were treated with infliximab in a French multicenter retrospective study, clinical remission was achieved by 8 patients (80 percent). The fast onset of infliximab was evident in the time required to achieve clearance of pustules; pustules cleared in a median of two days (range, one to eight days) [33].

A postmarketing surveillance study assessed the efficacy and safety of infliximab over six months. Among 56 patients with pustular psoriasis disease severity assessments, the proportion with moderate or severe pustular psoriasis fell from 25 and 7 percent, respectively, at baseline to 2 and 4 percent, respectively, at the final assessment, suggesting benefit [30].

The possibility that a single dose of infliximab may be sufficient is suggested by a case report documenting dramatic improvement in acute GPP within 24 hours following a single dose of infliximab followed by the initiation of methotrexate [34]. Infliximab has also been successfully used in combination with acitretin for the induction of rapid improvement while awaiting the onset of action of acitretin [44].

IL-17 inhibitors — IL-17 inhibitors used for GPP include secukinumab (an IL-17A inhibitor), ixekizumab (an IL-17A inhibitor), and brodalumab (an IL-17 receptor A inhibitor). Dosing generally reflects the recommended doses for plaque psoriasis. Optimal treatment regimens for GPP are unknown.

Examples of potential adverse effects of IL-17 inhibitors include injection site reactions and increased risk for upper respiratory tract infection, oral candidiasis, conjunctivitis, tinea infection, and inflammatory bowel disease. Although there has been concern for an increased risk for suicidal ideation and behavior in association with brodalumab therapy, a causative relationship has not been confirmed (see "Chronic plaque psoriasis in adults: Overview of management"):

●Secukinumab:

•Administration – Typical dosing for adults is 300 mg given subcutaneously once weekly at weeks 0, 1, 2, 3, and 4, followed by 300 mg every four weeks. Doses of 150 mg may be sufficient for some patients.

•Efficacy – Benefit of secukinumab (an anti-IL-17A monoclonal antibody) for GPP is suggested in a 52-week, open-label study in which 12 adults with GPP received secukinumab (150 mg once weekly at baseline; weeks 1, 2, 3, and 4; and then every four weeks, with the option to increase the dose to 300 mg in patients who showed minimal or no improvement) [45]. Eight patients also received nonbiologic systemic therapies for psoriasis, but doses of these agents could not be increased. At week 16 (the primary endpoint), 10 patients (83 percent) received clinical global impression ratings of "very much improved" or "much improved." One patient showed no improvement, and a second patient discontinued treatment prior to 16 weeks due to a protocol deviation. Improvement was rapid, with maximum improvement achieved within three weeks. Response rates remained high at 52 weeks.

Responses to secukinumab are also documented in case reports, including a patient with acute GPP who experienced complete resolution of pustulation within one week during treatment with secukinumab (300 mg given once weekly for three weeks) [46-52].

●Ixekizumab:

•Administration – Typical dosing for adults is 160 mg given subcutaneously at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12. Subsequently, 80 mg are given every four weeks.

•Efficacy – Ixekizumab (an anti-IL-17A monoclonal antibody) may be beneficial based upon a 52-week, open-label study in which 78 patients with plaque psoriasis, erythrodermic psoriasis, or GPP received ixekizumab (160 mg at week 0, then 80 mg every two weeks until week 12, then 80 mg every four weeks). At week 12, four of the five patients with GPP achieved 75 percent improvement in the Psoriasis Area and Severity Index score (PASI 75), and three patients achieved 90 percent improvement (PASI 90) [53]. This level of response was sustained with continued treatment over three years [54-56]. Concomitant systemic glucocorticoid therapy equivalent to less than or equal to 10 mg per day of prednisone was permitted.

Improvement in GPP with ixekizumab is also described in a case report and case series [57,58]. In a case series of 10 patients with refractory GPP treated with ixekizumab, all nine patients available for evaluation at week 12 achieved PASI 75 [57].

●Brodalumab:

•Administration – Typical dosing for adults is 210 mg given subcutaneously at weeks 0, 1, and 2 and then every two weeks. In the United States, brodalumab must be prescribed through a Risk Evaluation and Mitigation Strategy program due to concerns regarding risk for suicidal ideation and completed suicides in treated patients. (See "Chronic plaque psoriasis in adults: Overview of management".)

•Efficacy – A 52-week, open-label study evaluating the efficacy of the anti-IL-17 receptor A monoclonal antibody brodalumab (140 mg at day 1, weeks 1 and 2, then every two weeks, with the option to increase the dose to 210 mg) for GPP and erythrodermic psoriasis found that 11 of 12 patients with GPP achieved a clinical global impression of "improved" or "remission" by week 52 [59]. Improvement was rapid, with 9 of 12 patients achieving this status at week 2. Concomitant treatment with stable or decreasing doses of systemic methotrexate, vitamin A preparations, or glucocorticoids was permitted.

IL-23 inhibitors — Ustekinumab (an inhibitor of IL-12 and IL-23) and guselkumab (and inhibitor of IL-23) have been used for GPP. Dosing generally reflects the recommended doses for plaque psoriasis. Optimal treatment regimens for GPP are unknown:

●Ustekinumab:

•Administration – Dosing of ustekinumab is weight based. Typical dosing for adults ≤100 kg is 45 mg given subcutaneously at weeks 0, 4, and every 12 weeks thereafter. A 90 mg dose given in the same regimen is recommended for adults who weigh more than 100 kg.

•Efficacy – Case reports and case series have documented efficacy of ustekinumab in acute pustular psoriasis [60-63]. In one report, all four patients responded well to therapy, including one who harbored an IL36RN mutation. Three of the four patients also received low-dose acitretin [61]. The onset or worsening of pustular psoriasis following ustekinumab treatment has also been reported [64-67].

●Guselkumab:

•Administration – Typical dosing for adults is 100 mg given subcutaneously at weeks 0, 4, and then every 8 weeks.

•Efficacy – Guselkumab (a monoclonal antibody directed against the p19 subunit of IL-23) appeared beneficial in GPP and erythrodermic psoriasis in a 52-week, open-label study [68]. Ten patients with GPP were treated with 50 mg at weeks 0, 4, and every 8 weeks thereafter. The dose could be escalated to 100 mg at week 20 based on prespecified criteria, and patients were allowed to continue topical therapies and methotrexate. Seven of the patients with GPP achieved the primary study endpoint of treatment success (at least minimal improvement based upon a Clinical Global Impression rating at week 16), including four who achieved greater than minimal improvement. Two patients discontinued the study due to lack of response and a diagnosis of cutaneous squamous cell carcinoma. All eight patients who completed the study had treatment success at 52 weeks.

Adjunctive topical therapy — Because of the widespread nature of GPP, topical medications are primarily reserved for adjunctive therapy.

Topical therapies that have seemed useful for adjunctive therapy in case reports are similar to those used in chronic plaque psoriasis and include topical corticosteroids [69], combination therapy with a topical corticosteroid and topical vitamin D analog [70], and topical tacrolimus [71]. Topical corticosteroids are the topical agents we use most frequently.

The development of GPP in association with use of topical corticosteroids [72-74] and topical vitamin D analogs [72,75,76] has been reported. We aim to minimize this risk through focusing topical therapy on small areas of persistent or recalcitrant skin involvement [24,77].

A response of GPP to total body application of topical tacrolimus has been reported [78].

Second-line therapy for adults — When patients do not respond to or cannot tolerate a first-line therapy, we typically select one of the other acceptable first-line therapies. (See 'First-line pharmacologic therapy for adults' above.)

Patients for whom this is not an option may benefit from other approaches to therapy, such as psoralen plus ultraviolet A (PUVA) photochemotherapy or additional biologic therapies.

PUVA photochemotherapy generally is not used as a first-line therapy because of a delayed onset of action and the frequent clinic visits (eg, often three times per week) necessary for treatment. Limited evidence for efficacy contributes to the status of some antipsoriatic biologic agents as second-line, rather than first-line, therapies:

●Psoralen plus ultraviolet A (PUVA) photochemotherapy – PUVA photochemotherapy involves the administration of photosensitizing psoralen orally or topically prior to exposure to an ultraviolet A (UVA) light source. Because of a relatively slow onset of action, PUVA photochemotherapy is typically reserved for patients who have already achieved control of acute disease.

In an uncontrolled prospective study of eight patients with acute GPP, oral PUVA photochemotherapy (four times weekly) was associated with complete clearing of GPP in all patients within a mean of 13.5±10 treatment sessions [79]. Maintenance therapy (twice weekly PUVA treatments tapered to discontinuation if tolerated) was given upon complete remission, and seven patients remained in complete remission during follow-up periods of up to 1.5 years. The frequent clinic visits required for PUVA photochemotherapy make this a less favorable treatment option for some patients.

●Other biologic agents – Successful control of GPP during treatment with anti-TNF biologic agents other than infliximab (eg, adalimumab, certolizumab, etanercept) has been reported in small numbers of patients [33,80-86]. A phase 3 trial is evaluating efficacy of risankizumab, an IL-23 inhibitor.

In an open-label study in which 10 patients with GPP received adalimumab (40 or 80 mg every other week after an 80 mg initial dose), 7 patients achieved partial or complete improvement by week 16 [31]. In a retrospective study, two of three GPP flares treated with adalimumab progressed to clinical remissions, and clearance of pustules occurred within 7 and 28 days [33]. Of note, there are reports of TNF-alpha inhibitors inducing pustular psoriasis, including GPP [31].

●Combination therapy – Several case reports demonstrate efficacy in recalcitrant GPP when two or more classes of therapeutic agents are used in combination. Examples include etanercept and cyclosporine [26], infliximab and methotrexate [41,87], adalimumab and acitretin [88], adalimumab and methotrexate [89], infliximab and acitretin [44], secukinumab and colchicine [90], guselkumab and colchicine [90], acitretin and glycyrrhizin (a hepatoprotective constituent of Chinese herbal medicine) [91], and cyclosporine and PUVA photochemotherapy [25]. In addition, children have responded to combination therapy with narrowband ultraviolet B (UVB) and systemic therapies [92,93] as well as infliximab combined with methotrexate [87].

Other therapies — A variety of other therapies have been used for GPP, although concern for side effects or limited experience precludes a recommendation for the routine use of these therapies:

●Systemic glucocorticoids – Although systemic glucocorticoid therapy can lead to rapid improvement in GPP [28], the treatment must be used with caution because systemic glucocorticoids are implicated as potential inciting factors for GPP [24]. In addition, there is concern for the serious side effects from long-term glucocorticoid therapy. Thus, we do not typically use systemic glucocorticoids. In the event that systemic glucocorticoid treatment is given to obtain initial control of GPP, we suggest also initiating a second therapy in an attempt to reduce the likelihood of a disease flare during tapering and discontinuation of the systemic glucocorticoid. However, evidence to support this approach is lacking. The adverse effects of systemic glucocorticoids are reviewed separately. (See "Major adverse effects of systemic glucocorticoids".)

●Spesolimab – A 12-week, phase 2 trial suggests benefit of spesolimab, a monoclonal antibody that targets the IL-36 receptor [94]. In the trial, 53 adults with a moderate to severe GPP flare were randomly assigned in a 2:1 ratio to receive a single 900 mg subcutaneous dose of spesolimab or placebo on day 1, with options for open-label spesolimab on day 8 based upon response and subsequent open-label spesolimab as a rescue treatment. At day 8, 18 of 35 patients (54 percent) in the spesolimab group achieved a GPP Physician Global Assessment score of 0 (no visible pustules) compared with only 1 of 18 (6 percent) in the placebo group (difference 32 percentage points, 95% CI 2-53). Infections occurred in 17 percent of patients in the spesolimab group and 6 percent in the placebo group in week 1. Over 12 weeks, serious adverse events occurred in 6 of 51 patients (12 percent) who received at least one dose of spesolimab, including two patients with drug reaction with eosinophilia and systemic symptoms (DRESS). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●Other – Several case reports document the successful use of granulocyte and monocyte apheresis for the treatment of refractory GPP, including a report of use in a patient harboring the IL36RN mutation [95-102]. Other treatments that have been reported to be effective for GPP in case reports include anakinra [98,103,104], canakinumab [105], mycophenolate mofetil [106], oral zinc [107], dapsone [108], and apremilast [109]. It remains to be seen whether anakinra is primarily effective for GPP associated with deficiency of the interleukin-36-receptor antagonist (DITRA). (See 'IL36RN mutations' below.)

The efficacy of other biologic agents for GPP is unclear. Clinical trials are underway for several therapies.

Special populations

Children — Childhood GPP is rare, contributing to a paucity of data on the efficacy and safety of treatments for GPP in children. As in adults, oral retinoids, cyclosporine, methotrexate, TNF-alpha inhibitors, secukinumab, and ustekinumab have been used for the treatment of children [110].

Acute generalized pustular psoriasis — No randomized trials have evaluated the efficacy of treatments for acute GPP in children. Treatment selection is primarily based upon case reports or case series that suggest efficacy of these drugs in children with GPP and experience with these agents for other forms of psoriasis in children [110]. Benefit has been described for oral retinoids [16,77,111-115], cyclosporine [27,93,116-120], methotrexate [113,121,122], etanercept [87,123-126], adalimumab [80,127,128], infliximab [123,126,129], and secukinumab [130-132]. We consider the following agents appropriate initial treatment choices for children with GPP:

●Tolerable, nondisabling disease:

•Acitretin (less than 1 mg/kg per day)

•Methotrexate (0.2 to 0.4 mg/kg per week)

•Etanercept (<63 kg: 0.8 mg/kg once per week; ≥63 kg: 50 mg once per week)

●Severe, acute disease:

•Cyclosporine (1 to 3 mg/kg per day)

•Infliximab (5 mg/kg at weeks 0, 2, and 6, then every six to eight weeks if continuation of therapy is needed)

•Secukinumab (for children <50 kg, 75 mg; for children ≥50 kg, 150 mg given at weeks 0, 1, 2, 3, and 4 and then every 4 weeks)

As in adults, children requiring cyclosporine or infliximab for severe disease may be transitioned to other therapies after achievement of control of disease [133]. Long-term treatment with cyclosporine is not recommended due to risk for serious side effects. (See "Pharmacology of calcineurin inhibitors", section on 'Side effects'.)

In particular, randomized trials supporting the efficacy and safety of etanercept for moderate to severe plaque psoriasis in children have contributed to use of etanercept as a first-line therapy in the pediatric population [134-136]. However, evidence for efficacy of etanercept in GPP is very limited, and etanercept is not typically used as a first-line therapy in adults.

Given the contraindication for pregnancy during acitretin treatment and for three years after drug discontinuation, the use of acitretin in female children and adolescents must be considered carefully. Successful treatment with isotretinoin in place of acitretin has been reported in an adolescent female [16]. A slight risk for skeletal toxicity has been observed in children treated with high doses of oral retinoids for disorders of keratinization [137].

Additional therapies that may be useful in the treatment of pediatric acute GPP based upon case reports include narrowband UVB phototherapy in conjunction with systemic therapy [92,93], adalimumab [80], and the combination of infliximab and methotrexate [87]. Also, an infant with GPP associated with DITRA has responded to anakinra [138], and an adolescent with DITRA achieved a rapid clinical response and sustained remission during treatment with secukinumab [48].

Generalized annular pustular psoriasis — Topical corticosteroid therapy may be effective for the treatment of children with annular pustular psoriasis, which exhibits less severe manifestations than acute GPP [5]. In addition, topical compresses, wet wraps, or oatmeal baths may be helpful for soothing the skin lesions [5,139].

Topical therapy for annular pustular psoriasis is less practical when a large proportion of the body surface is affected. Patients who cannot be managed only with topical therapy can be treated with systemic agents. Case reports suggest that oral retinoids, oral dapsone, and methotrexate can be effective for this variant [5].

Pregnant women — The management of pustular psoriasis in pregnancy (impetigo herpetiformis) is reviewed separately. (See "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy'.)

IL36RN mutations — Growing understanding of the molecular basis of GPP associated with IL36RN mutations may aid in therapeutic decisions for patients with this type of GPP [140]. Evidence suggests that some cases of GPP (or acute generalized exanthematous pustulosis [AGEP]) may actually represent a new genetic autoinflammatory disease based on mutations in the IL36RN gene, which encodes the IL-36 receptor antagonist. This disease is known as DITRA. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".)

Patients with IL36RN mutations upregulate IL-1 in response to IL-36 stimulation. Case reports documenting successful treatment of GPP in patients with IL36RN mutations with anakinra, an IL-1 receptor antagonist, support the importance of this pathway [104,138]. In addition, preliminary findings of clinical trials suggest that treatment with IL-1 antagonists can improve GPP (picture 2) [105,141]. As more data accumulate, IL-1 blockade may become the treatment of choice for patients who harbor the genetic mutation.

The beneficial effects of systemic therapy, such as acitretin, TNF-inhibiting drugs, and anti-IL-17/23 antibodies, for GPP appear independent of the presence of the IL36RN mutation [42,61,125,142-144]. Whether agents targeting the IL-36 pathway or IL-1 will be more effective and/or safer for patients with the mutation remains to be determined.

LOCALIZED PUSTULAR PSORIASIS — 

The approach to the treatment of pustular psoriasis differs from generalized pustular psoriasis (GPP). Local treatment generally is used as first-line treatment, with systemic therapies reserved for patients who fail to respond well to local therapy.

Acrodermatitis continua of Hallopeau — Acrodermatitis continua of Hallopeau (ACH) is a rare, chronic, localized form of pustular psoriasis that primarily involves one or more extremity digits (picture 3). ACH is often poorly responsive to therapy. (See "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Acrodermatitis continua of Hallopeau'.)

A variety of local and systemic therapies have been utilized for ACH with variable results. Data on the treatment of this rare disease are primarily limited to case reports and case series. Topical corticosteroids, topical tacrolimus, topical calcipotriol (alone or in combination with topical corticosteroids or topical tacrolimus), topical mechlorethamine hydrochloride, topical fluorouracil, psoralens plus ultraviolet A (PUVA) photochemotherapy, narrowband ultraviolet B (UVB) phototherapy, ultraviolet A1 (UVA1) phototherapy, and brachytherapy are among the local treatments documented as effective in individual patients with ACH [145-148]. Systemic therapies have included oral retinoids, methotrexate, cyclosporine, systemic glucocorticoids, methotrexate and propylthiouracil, infliximab, adalimumab, etanercept, ustekinumab, tocilizumab, secukinumab, and anakinra [145,149-155]. The efficacies of these interventions have not been compared, and the best approach to treatment is unclear.

Our initial choice for treatment of ACH is typically a superpotent topical corticosteroid (eg, halobetasol or clobetasol), which we instruct the patient to apply to the affected areas once to twice daily for two to four weeks (table 1). Preferably, the patient should apply the medication under an occlusive dressing at night, particularly during the first week of therapy. Plastic wrap is commonly used as an occlusive dressing. Alternatively, occlusion can be applied using damp cloth covered by dry cloth.

If a good response to treatment occurs, the frequency of application can be tapered as tolerated to a frequency as low as once or twice per week. Alternatively, we prescribe a topical vitamin D analog (eg, topical calcitriol or calcipotriene) in conjunction with the superpotent topical corticosteroid and instruct the patient to apply the topical corticosteroid followed immediately by the vitamin D analog once to twice daily for two to four weeks. Once sufficient improvement is achieved, we taper the topical corticosteroid as tolerated and continue treatment with the vitamin D analog. A commercial product containing both betamethasone dipropionate and calcipotriene is available.

When patients fail to respond adequately to topical therapy, we proceed to local phototherapy or systemic therapy, although we usually continue to use topical corticosteroids as adjunctive therapy. PUVA photochemotherapy, narrowband UVB, and UVA1 therapy have appeared effective for ACH [145,147,148]. We often use acitretin (0.5 to 1 mg/kg per day) as our first-line systemic treatment, with methotrexate and cyclosporine as alternatives. For patients with severe disease and who are at risk for nail loss, we tend to prescribe biologic therapy.

If a patient fails to improve with traditional systemic therapies or presents with severe ACH, we often proceed to a biologic tumor necrosis factor (TNF)-alpha inhibitor, an anti-interleukin (IL) 12/23 therapy, or an anti-IL-17 therapy, such as adalimumab, infliximab, ustekinumab, ixekizumab, brodalumab, or secukinumab [156-162]. The response to biologic therapy varies, and data are insufficient for conclusions on the most effective therapies [163,164].

Palmoplantar pustulosis — Palmoplantar pustulosis is a chronic condition characterized by the development of yellow to brown pustules, scale, and patchy erythema on the palms or soles. It is controversial whether palmoplantar pustulosis is a localized variant of pustular psoriasis (palmoplantar pustular psoriasis) or a separate entity. The treatment of palmoplantar pustulosis is reviewed separately. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis" and "Palmoplantar pustulosis: Treatment".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psoriasis".)

SUMMARY AND RECOMMENDATIONS

●Disease overview – Generalized pustular psoriasis (GPP) is an uncommon form of psoriasis characterized by the development of widespread pustules and erythematous plaques on the skin. The goals of treatment are to improve skin manifestations, alleviate systemic symptoms, and prevent serious or life-threatening complications of this disease. (See 'Generalized pustular psoriasis' above.)

●Approach to therapy – Treatment options for adults with GPP include topical therapies, systemic therapies, and phototherapy. Most patients require systemic therapy. Topical therapies are primarily used as adjuncts to systemic therapy (see 'Approach to therapy' above):

•Important interventions – As part of the initial management of patients with GPP, the need for hospitalization should be assessed. In addition, the patient's medical history should be reviewed for drugs that may contribute to the development of GPP. (See 'Approach to therapy' above.)

•Initial treatment for adults – The approach to the treatment of GPP is influenced by the acuity and severity of symptoms. For adult patients with relatively stable disease, we suggest acitretin or methotrexate as initial therapy (Grade 2C). For adult patients with severe, acute GPP, we suggest initial therapy with fast-acting therapies, such as cyclosporine, infliximab, or select anti-interleukin (IL) 17/23 therapies (Grade 2C). (See 'First-line pharmacologic therapy for adults' above.)

•Initial treatment for children – Data on the treatment of acute GPP in children are very limited. Options for first-line therapy include acitretin, cyclosporine, methotrexate, etanercept, infliximab, and secukinumab. Some children with annular pustular psoriasis can be managed with topical treatment. (See 'Children' above.)

•Other therapies – Other therapeutic agents that may be effective in adults with GPP include psoralen plus ultraviolet A (PUVA) photochemotherapy, adalimumab, and etanercept. Combination therapy with more than one treatment can also be attempted. (See 'Second-line therapy for adults' above.)

•Role of systemic glucocorticoids – Systemic glucocorticoids can induce rapid improvement in GPP but have been identified as potential inciting factors for this disease. We do not usually use systemic glucocorticoids for the treatment of GPP. (See 'Other therapies' above.)

●Role of IL36RN mutations – Increasing knowledge about the pathogenesis of GPP associated with IL36RN mutations may lead to new therapeutic options for this form of GPP. (See 'IL36RN mutations' above.)

●Acrodermatitis continua of Hallopeau – Acrodermatitis continua of Hallopeau (ACH) is a rare form of localized pustular psoriasis that primarily affects the extremity digits and is often refractory to treatment. Data on treatments for ACH are limited to case reports. We suggest a superpotent topical corticosteroid as initial treatment (Grade 2C). (See 'Acrodermatitis continua of Hallopeau' above.)